4-benzazonine derivatives and process for preparation thereof

ABSTRACT

Novel 4-benzazonine derivatives and their salts, and processes for the preparation thereof are disclosed. These 4-benzazonine derivatives are represented by the following general formula: ##STR1## wherein R stands for --H, --OH or a lower alkoxy group such as --OCH 3 , R 1  designates --H or a lower alkyl group such as --CH 3  and --CH 2  CH 3 , R 2  indicates --H or a lower alkyl group such as --CH 3 , R 3  stands for --H, a linear or branched, saturated or unsaturated alkyl group having 1 to 4 carbon atoms, a mono- or di-hydroxy lower alkyl group such as --CH 2  OH and ##STR2## a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms or a substituted or unsubstituted aromatic hydrocarbon group having 6 to 8 carbon atoms, and R 4  designates --H, --OH or ═ 0. These compounds have medicinal effects, especially therapeutic activities on the central nervous system, such as analgesic, antitussive and sedative activities.

This is a division of Ser. No. 467,520 filed May 6, 1974, now U.S. Pat. No. 4,008,219 issued Feb. 15, 1977.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel 4-benzazonine derivatives and their salts having therapeutical activities on the central nervous system with low toxicity, and to processes for the preparation of these derivatives and salts.

2. Description of the Prior Art

It is known that 3-benzazocine derivatives which are considered to be compounds having a morphinan structure in which the ring C is cleft have an analgesic activity. Among these derivatives, 1, 2, 3, 4, 5, 6-hexahydro-3-(3-methyl-2-butenyl)-6, 11-dimethyl-8-hydroxy-2, 6-methano-3-benzazocine generally called "pentazocine"; Journal of Medicinal Chemistry, 7, 123 (1964) and Chemical Abstracts, 58, 2440^(b) (1963) is used for therapeutic purposes. Morphinan and pentazocine have structures represented by the following formulae: ##STR3##

SUMMARY OF THE INVENTION

As a result of our research work, we established processes for the preparation of 4-benzazonine derivatives having a structure in which the ring C of morphinan is cleft or removed, the ring D is a 7-membered ring and the ring B has a hydroxyl group, and we have now arrived at this invention based on the finding that these derivatives have pharmacological activities similar to those of pentazocine.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to 4-benzazonine derivatives and their pharmacologically active salts, and to processes for the preparation thereof.

4-Benzazonine derivatives of this invention are novel compounds represented by the following general formula (1): ##STR4## wherein R stands for hydrogen, a hydroxyl group or a lower alkoxy group having 1 to 3 carbon atoms, R₁ designates hydrogen or a lower alkyl group having 1 to 3 carbon atoms, R₂ indicates hydrogen or a lower alkyl group having 1 to 2 carbon atoms, R₃ stands for hydrogen, a linear or branched, saturated or unsaturated alkyl group having 1 to 4 carbon atoms, a mono- or di-hydroxyalkyl group having 1 to 2 carbon atoms, a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms or a substituted or unsubstituted aromatic hydrocarbon group having 6 to 8 carbon atoms, and R₄ designates hydrogen, --OH or ═ 0. This invention relates to novel 4-benzazonine derivatives represented by the above general formula (1) and their salts, and to processes for the preparation thereof.

Starting substances necessary for the synthesis of compounds represented by the general formula (1) can easily be prepared by the methods described in The Journal of Organic Chemistry, 25, 1386 (1960), Journal of Medicinal Chemistry, 13, No. 4, 631 (1970), and Chemical & Pharmaceutical Bulletin, 21, No. 5, 1060 (1973). For instance, starting substances for the synthesis of compounds represented by the following formula ##STR5## can be prepared through reactions shown by the following reaction formulae: ##STR6##

Typical instances of compounds of this invention and of preparation processes will now be described.

1. Process for the preparation of a compound represented by the following formula: ##STR7## (this compound will hereinafter be referred to as "compound A").

A solvent-soluble salt of an α-tetralone represented by the following general formula: ##STR8## wherein R, R₁ and R₂ are as defined above, and Z indicates an inorganic acid such as hydrochloric acid or sulfuric acid, such as 4-(N-methylaminoethyl)-3,4-dihydronaphthalen-1(2H)-one, is subjected to the Mannich reaction with formaldehyde, preferably formalin, in the presence of a solvent such as water and a lower alcohol, e.g., methanol, ethanol or propanol, preferably methanol, to thereby effect ring closure and form a 7-membered ring, whereby the compound A, namely a 4-methyl-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one derivative, is obtained.

The amount of the solvent used for the Mannich reaction is sufficient if the α-tetralone derivative salt and formaldehyde are completely dissolved in the solvent at room temperature, but it is preferred that the amount of the solvent be 10 to 40 times the amount of the reactants on the weight basis. In order to prevent occurrence of side reactions, it is preferred that the reaction be carried out at a low temperature for a short time. More specifically, it is desired that the reaction be conducted at 20° to 70° C. for 20 to 70 hours. Formaldehyde is used in an amount equivalent to the amount of the α-tetralone derivative or in an excess amount. In general, it is advantageous that the amount of formaldehyde be about 2 to about 10 times the equivalent amount.

2. Process for the preparation of a compound represented by the following formula: ##STR9## (this compound will hereinafter be referred to as "compound B").

A compound B, for example, 4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol, can be obtained by reducing a compound A, for example, 4-methyl-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one.

For accomplishing this reduction, it is preferred to adopt a method using as a reducing agent a complex metal hydride such as LiAlH₄ or NaBH₄. Use of a solvent is indispensable for this reduction. Anhydrous ether, tetrahydrofuran and dioxane are used when LiAlH₄ is employed as the reducing agent, and when NaBH₄ is employed as the reducing agent, a lower alcohol, preferably methanol, is used as the solvent. The amount of the solvent used is not a critical factor influencing the progress of the reaction, and the solvent may be used in such an amount as adopted in customary methods. It is preferred that the amount of the solvent be 20 to 30 times the amount of LiAlH₄ or NaBH₄ on the weight basis.

In the case of LiAlH₄, it is preferred that the reduction be carried out at a temperature ranging from 0° C. to the boiling point of the solvent used. The reaction time is varied depending on the boiling point of the solvent used, but in general, the reaction is carried out for 1 to 15 hours. For example, good results can be obtained when the reaction is carried out for 4 to 8 hours by employing dioxane as the solvent.

In case the reduction is performed by employing NaBH₄, it is preferred that the reaction be conducted at 10° to 30° C. for 1 to 3 hours, though the reaction can proceed even at -10° C.

The complex metal hydride is used in an amount equivalent to the compound A or in an excess amount, preferably up to 2 to 3 times the equivalent amount.

As another method for the reduction, there can be employed a method in which known reducing agents consisting of a combination of an alkali or alkaline earth metal, preferably sodium, and an alcohol, or known aluminum alcoholates such as aluminum isopropylate are employed. In this method, the reducing agent is used in an amount of 2 to 6 times the equivalent amount according to conventional techniques.

As still another method for the reduction, there can be employed a method in which hydrogenation is performed with use of a known hydrogenation catalyst such as nickel, platinum and palladium catalysts. In this method, the catalyst is used in the finely divided state alone or in the form supported on a carrier such as activted carbon, diatomaceous earth and barium sulfate. The amount used of the catalyst is not critical but can be changed within a broad range. This hydrogenation reaction is conducted under atmospheric pressure or slightly elevated pressure (preferably 1 to 3 atmospheres) under agitation. High reaction temperatures are likely to cause side reactions to occur, and therefore, it is preferred that the reaction be carried out at a temperature ranging from room temperature to about 60° C. It is desired that hydrogen is absorbed in the equivalent amount or an amount slightly in excess over the equivalent amount. Absorption of too excessive an amount of hydrogen is not preferred because side reactions occur and the yield of the intended product is reduced.

3. Process for the preparation of a compound represented by the following general formula: ##STR10## (this compound will hereinafter be referred to as "compound C").

A compound C, for example, 4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-4-benzazonine, can be prepared by reducing a compound B, for example, 4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.

The removal of the OH group at the 7-position can be accomplished by known methods, such as the Clemmensen reduction method, the method using hydrogen activated by a catalyst and the method in which the OH group is first replaced by a halogen, for example, Cl, Br and I, and dehalogenation is then performed with use of a metal such as sodium, zinc, magnesium, iron or tin. Each of these known methods, however, is defective in that the reaction course is long or a long time is required for completion of the reduction. Furthermore, in these known methods, the isolation of the intended product from the reaction mixture liquid, which is conducted after completion of the reaction, involves complicated operations.

In the synthesis of the compound C, it has been found that the reduction is performed with use of hydriodic acid and red phosphorus. The object can be attained when hydriodic acid and red phosphorus are used in equivalent amounts, but it is preferred that they be used in slight excess amounts. In general, it is desired that hydriodic acid be used in an amount of 2 to 4 moles per mole of the compound B and red phosphorus be used in an amount of 1 to 2 atoms per mole of the compound B.

The concentration of hydriodic acid has influence on the reaction rate and the yield of the intended product, and when the concentration of hydriodic acid is lower than 10%, the reaction time is much prolonged. It is preferred that the concentration of hydriodic acid be within a range of 20 to 57% (the concentration of hydriodic acid for industrial use). The reaction is carried out at 60° to 160° C. under atmospheric or elevated pressure. It is preferred that the reaction be conducted at 100° to 120° C. under atmospheric pressure, and in this case the reaction is completed in from about 1 to about 6 hours.

It has been found that when the reaction is carried out in the presence of a solvent including acetic acid and further apply the compound B in which R stands for --OH or --OCH₃, the yield of the intended compound C can be increased. It is desired that acetic acid be used in an amount of 1 to 10 moles per mole of the compound B. It is not advantageous to use too little or too great an amount of acetic acid.

4-I process for the preparation of a compound represented by the following general formula: ##STR11## (this compound will hereinafter be referred to as "compound D").

The compound D can be prepared by reacting a 4-benzazonine derivative represented by the following formula: ##STR12## (this compound will hereinafter be referred to as "starting compound K") with a compound represented by the general formula X--CH₂ --R₃ in which X stands for a halogen atom, an alkyl--SO₂ --O-- or aryl--SO₂ --O-- group and R₃ is as defined above [method (a)], by reacting the starting compound K with a compound represented by the general formula ##STR13## in which X and R₃ are as defined above, and reducing the resulting reaction product with a complex metal hydride [method (b)], and by reacting the starting compound K with a compound represented by the general formula ##STR14## in which R₃ is as defined above, in the presence of formic acid or hydrogen activated by a catalyst [method (c)].

The starting compound K to be used in the foregoing methods (a), (b) and (c) can be prepared, for example, according to the reaction represented by the following reaction formula: ##STR15##

The above methods (a), (b) and (c) will be described below.

Method (a)

The starting compound K is reacted with an alkylating agent of the formula X--CH₂ --R₃ in the equivalent amount or in an amount slightly excessive over the equivalent amount in the presence of an appropriate acid binder. As the acid binder, there are employed amines such as tirethylamine, dicyclohexylethylamine or the like, and sodium carbonate, potassium carbonate, sodium bicarbonate or the like. It is preferred that the amount of the acid binder used be 1.5 to 2 times the equivalent amount.

This reaction is preferably accomplished in the presence of a solvent such as ether, tetrahydrofuran, dioxane, dimethylformamide, chloroform, benzene, toluene, alcohol or a mixture of two or more of these solvents. The amount used of the solvent is not particularly critical, but it is desired that the solvent be used in an amount 1 to 10 times the total amount of the reactants used on the weight basis.

The reaction temperature can be changed within a broad range. For instance, it is preferred that the reaction be carried out at a temperature ranging from 0° C. to the boiling point of the solvent used.

The reaction is completed within 0.5 to 5 hours, but in case a lower alkyl chloride or bromide is used, it is preferred that the reactants be heated at 50° to 100° C. in a sealed tube under shaking for 1 to 10 hours. Use of a lower alkyl iodide is advantageous, because the reaction is accomplished by conducting heating under reflux at atmospheric pressure.

Method (b)

The starting compound K is reacted with a carboxylic acid halide represented by the formula ##STR16## preferably a carboxylic acid chloride, in the presence of a dehydrohalogenation agent to form a 4-acyl compound represented by the following general formula: ##STR17## wherein R, R₁, R₂ and R₃ are as defined above, and then, the so formed 4-acyl compound is reduced with a complex metal hydride such as lithium aluminum hydride or di-isobutyl aluminum hydride to form a compound D.

The 4-acyl compound of the above general formula is synthesized according to the Schotten-Baumann process. It is desired that this reaction be carried out in the presence of a dehydrohalogenation agent such as an organic amine, e.g., triethylamine, dicyclohexylethylamine or the like by employing a solvent such as ether, benzene, toluene or chloroform.

In the subsequent reduction, it is preferred that lithium aluminum hydride be used as the complex metal hydride. The complex metal hydride is used in the equivalent amount or preferably in an excessive amount, namely in an amount up to 4 times the equivalent amount.

This reduction reaction is carried out in such a solvent as ether, tetrahydrofuran, dioxane or the like. It is preferred that the solvent be used in such amount that the 4-acyl compound is completely dissolved at the reaction temperature.

The reaction temperature is adjusted within a range of from 0° C. to the boiling point of the solvent used.

The reaction time is varied depending on the reaction temperature, but in general, the reaction is completed within about 12 hours.

Method (c)

The reaction between the starting compound K and an aldehyde of the general formula ##STR18## is the presence of formic acid proceeds in an aqueous solution or in the absence of a solvent. In the case of acetaldehyde or propylaldehyde, is preferred that the reaction be conducted in an aqueous solution, and in the case of other aldehydes it is preferred that the reaction be carried out in the absence of a solvent. The aldehyde is used in the equivalent amount or an excessive amount. It is desired that the aldehyde be used in an excess amount of up to 3 moles per mole of the starting compound K. Formic acid is used in an excess amount, preferably up to 10 moles per mole of the starting compound K. The reaction temperature is 50° to 200° C., preferably 80 to 150° C. It is desired that the heating be conducted for 1 to 4 hours.

As a modification of this method, there is mentioned a reductive alkylation method using catalytically activated hydrogen. The aldehyde is used in the equivalent amount or in an excess amount preferably in an excess amount of up to 2 moles per mole of the starting compound K. This reaction is carried out in the presence of an appropriate solvent, for example, alcohols, preferably methanol or ethanol. It is advantageous to use the catalysts such as Raney nickel, palladium and platinum. It is preferred that palladium and platinum be used in the state dispersed on a carrier such as active carbon and diatomaceous earth. In this case, the preferred catalyst content is within a range of from 5 to 10%, though the amount of the catalyst is not particularly critical. The hydrogenation is conducted under atmospheric pressure or slightly elevated pressure, preferably 1 to 3 atmospheres, under agitation. Since a high tempeature causes side reactions, it is preferred that the hydrogenation be conducted at a temperature ranging from room temperature to 60° C. It is desired that the reaction be conducted so that the amount absorbed of hydrogen approximates the equivalent amount.

4-II Another process for the preparation of the Compound D.

When a compound represented by the following formula: ##STR19## is reduced with active hydrogen, the compound D can be obtained.

This process is substantially accomplished in one step, and the compound I can be prepared in a short time. Accordingly, this process is advantageous from the industrial viewpoint.

Various catalysts can be used for activation of hydrogen, and a palladium catalyst is most preferred among them. The palladium catalyst is used in the finely dispersed state alone or in the form supported on a carrier such as activated carbon, barium sulfate or the like.

The amount of the catalyst is not particularly critical but can be varied within a broad range.

A polar solvent such as acetic acid, ethanol or methanol is preferably used as the reaction solvent. It is suitable to use the solvent in an amount 3 to 100 times the amount of the compound to be reduced on the weight basis.

The hydrogenation is accomplished by introducing hydrogen into the reaction mixture under shaking or agitation at atmospheric pressure.

It is preferred that the reaction be conducted at a temperature ranging from room temperature to the boiling point of the solvent used. It is permissible to conduct the heating in two stages, if necessary.

The reduction proceeds substantially in the following manner: ##STR20## when the reaction is conducted at room temperature, an intermediate 7-hydroxy compound is mainly formed. If the intermediate is further reduced at a temperature not lower than 50° C., the intended compound D can be obtained. Thus, the process 4-II of this invention includes an embodiment where the compound D is formed through an intermediate.

The reaction time can be changed within a broad range depending on the reaction conditions, and a reaction time of 5 to 10 hours is sufficient.

It has been found that addition of a strong acid such as hydrochloric acid, perchloric acid or sulfuric acid accelerates this reaction and results in increase of the intended compound D. It is preferred that such strong acid be added in an amount of 1 to 5 moles per mole of the compound to be reduced.

The reaction is carried out at a pressure ranging from atmospheric pressure to about 10 atmospheres. Though the reaction pressure has no substantial influence on the reaction rate or the yield of the intended compound B, it is preferred that the reaction be conducted at atmospheric pressure.

5-I Process for the preparation of a compound represented by the following formula: ##STR21## (this compound will hereinafter be referred to as "compound E").

A 4-benzazonine derivative represented by the following general formula: ##STR22## (this compound will hereinafter be referred to as "starting compound L") is converted to the compound E by reacting the starting compound L with a compound represented by the general formula X-CH₂ -R₃ in which X and R₃ are as defined above [method (a)] or by reacting the starting compound L with a compound represented by the general formula ##STR23## in which X and R₃ are as defined above and reducing the resulting reaction product with a complex metal hydride [method (b)]. Conditions adopted in these methods (a) and (b) are substantially identical with those adopted in methods (a) and (b) of the process 4-I. The starting compound L is prepared, for example, in the following manner: ##STR24##

5-II Another process for the preparation of a compound E.

A compound E can be prepared by reducing a compound represented by the following general formula (hereinafter referred to as "compund F"): ##STR25## wherein B stands for --CO-- or --CH₂ --.

The reduction of the compound F is preferably accomplished by a method using as a reducing agent a complex metal hydride such as lithium aluminum hydride and sodium boron hydride or by a method in which hydrogenation is conducted with use of such a catalyst as platinum or palladium.

The complex metal hydride is used in an amount slightly in excess of the equivalent amount of the compound F, preferably 1.5 to 4 times the equivalent amount. This reduction is conducted in an appropriate solvent. For instance, ether, tetrahydrofuran, dioxane or the like is used in the case of lithium aluminum hydride, and methanol, ethanol or the like is used in the case of sodium boron hydride.

The amount used of the solvent is not particularly critical, but it is necessary that the solvent be used at least in such an amount as to completely dissolve the compound F at the reaction temperature.

The reaction temperature can optionally be chosen within a range of -10° C. to the boiling point of the solvent used.

The reaction time is varied depending on the reaction temperature, and in general, the reaction is completed within 24 hours.

In the case of the hydrogenation reduction using platinum, palladium or the like as a catalyst, the hydrogenation catalyst is used in the finely dispersed state alone or in the form supported on a carrier such as activted carbon and barium sulfate. The amount of the catalyst used is not particularly critical but can be varied within a broad range.

Acetic acid, ethanol or methanol is preferably used as a solvent, and it is preferred that the solvent be used in an amount 30 to 100 times the amount of the compound to be reduced on the weight basis.

The reduction is accomplished by introducing hydrogen gas into the reaction mixture under shaking or agitation at atmospheric or elevated pressure. The reaction proceeds relatively smoothly at atmospheric pressure and room temperature. It is preferred that hydrogen be absorbed in an amount slightly greater than the calculated equivalent amount.

It has been found that when this reaction is conducted under high temperature and high pressure conditions, side reactions are caused to occur and the yield of the intended product is reduced. It has also been found that the reaction is accelerated if such a compund as hydrochloric acid or perchloric acid is present in the solvent.

The compound F can be prepared by applying the above-mentioned method 4-I (a) or 4-I (b) to a compound represented by the following general formula: ##STR26## (this compound will hereinafter be referred to as "starting compound M").

This compound M can be prepared, for example, in the following manner: ##STR27## 6. Process for the preparation of a compound represented by the following general formula:

(this compound will hereinafter be referred to as "compound G").

This compound F can be prepared by methoxylating a compound represented by the following general formula: ##STR28## (this compound will hereinafter be referred to as "compound C'").

The methoxylation of the hydroxyl group at the 10-position, namely the phenolic hydroxyl group, is generally performed with use of dimethyl sulfate or methyl p-toluene-sulfonate. However, in this case, side reactions readily occur and the yield of the intended compound is reduced.

If the methoxylation is carried out with use of diazomethane or trimethylphenyl ammonium hydroxide, the intended product can be obtained in a high yield in the pure form.

In case diazomethane is used for the methoxylation, the object can be attained if it is used in an amount equivalent to the compound C', namely 1 mole per mole of the compound C', but it is preferred that diazomethane be used in an excess amount of up to about 2 moles per mole of the compound C'.

The presence of a solvent is not indispensable, but in the case of diazomethane, in view of the handling it is preferred that ether or chloroform be used as a solvent. The advance of the reaction is not influenced by the amount of the solvent used.

Preferred reaction temperatures are within a range of from - 10° to 10° C. The reaction is completed within about 1 to about 10 hours, and during the reaction there is observed generation of nitrogen gas. Since diazomethane is a very poisonous gaseous compound, it is desired that the resulting product mixture be treated after it has been allowed to standstill for 10 to 20 hours for complete decomposition of diazomethane.

As pointed our above, diazomethanne is a poisonous gaseous substance. It is also explosive. Therefore, it is possible to adopt a method in which a diazomethane-forming compound such as nitrosomethyl urea, nitrosomethyl urethane or N-nitroso-β-methylamino-iso-butyl methylketone is present in ether or a lower alcohol, preferably ether or methanol, and the reaction is conducted while generating diazomethane by adding hydroxide, potassium hydroxide or sodium alcoholate to the mixture. In this case, it is preferred that the reaction be carried out at -10 to 10° C.

In case the methoxylation is performed with use of trimethylphenyl ammonium hydroxide, the heating is conducted in the absence or presence of a solvent by employing trimethylphenyl ammonium hydroxide in an amount of 1 to 2 moles per mole of the compound C'. A method in which dimethylaniline formed as a by-product is removed by steam distillation is preferably adopted.

This reaction is allowed to proceed at temperatures ranging from about 60° to about 200° C., and the reaction time is generally within a range of 30 minutes to 2 hours. It is preferred that the reaction is carried out at a temperature of about 100° to about 110° C. for 1 to 4 hours.

In a modification of this process, the trimethylphenyl ammonium hydroxide is used in the following manner. More specifically, sodium hydroxide, potassium hydroxide or an alkali metal alcoholate is added to a methanol or ethanol solution of a trimethylphenyl quaternary ammonium salt (inclusive of halides and p-toluenesulfonates), the precipitated sodium or potassium salt is removed by filtration, and the methanol or ethanol solution of trimethylphenyl ammonium hydroxide obtained as the filtrate is used directly for the reaction.

The compound C' can be prepared, for example, in the following manner: ##STR29##

7. Process for the preparation of a compound represented by the following general formula: ##STR30## (this compound will hereinafter be referred to as "compound H").

This compound H can be prepared by reacting a compound represented by the following general formula: ##STR31## (this compound will hereinafter be referred to as "compound I") with a mineral acid, for example, hydrobromic acid, hydriodic acid or sulfuric acid.

As the mineral acid, there are preferably employed hydrohalogenic acids, and use of hydrobromic acid is most preferred because the resulting 4-benzazonine derivative is readily crystallized in the form of a hydrobromide.

In this reaction, the amount of the acid used, the reaction time and the heating time are not particularly critical, but in general, it is preferred that the reaction be conducted under reflux for 30 minutes to 1 hour by employing the acid in an amount 5 to 10 times the amount of the compound I. It is desired that the reaction mixture be heated so that it is kept refluxed. However, if the --CH₂ --R₃ of the compound I is an unstable group such as a cyclopropylmethyl or a cyclobutyl methyl group, it is preferred that the amount used of the acid by relatively lowered and the heat refluxing be conducted under mild conditions for a short time.

The compound I used as the starting compound in this process is included in the scope of the intended product of this invention, and it can be prepared, for example, by the process 4-I.

8. Process for the preparation of a compound represented by the following general formula: ##STR32## (this compound will hereinafter be referred to as "compound J").

This compound J can be prepared by reducing a compound A with activated hydrogen.

As regards the reduction of the > C═O group at the 7-position to a > CH₂ group, there is known a two-stage method comprising reducing the > C=O group with, for example, a complex metal hydride to convert it to a > CH-- OH group and further reducing it with hydriodic acid and red phosphorus. This method, however, is defective in that the reaction course is very long and complicated operations are included.

In the process of this invention, activated hydrogen is used for the reduction. Known catalysts for the catalytic reduction can be used for activation of hydrogen, and palladium is most preferred among them. The catalyst is used in the finely dispersed state alone or in the form supported on a carrier such as activated carbon or barium sulfate. The amount of the catalyst used is not particularly critical but can be changed within a broad range. Polar solvents such as acetic acid, ethanol and methanol are preferably employed as the reaction solvent, and it is preferred that the solvent be used in an amount 30 to 100 times the amount of the substance to be reduced on the weight basis. The catalyst hydrogenation is performed by introducing hydrogen gas into the reaction mixture under shaking or agitation at atmospheric or elevated pressure.

It is preferred that the reaction is carried out at a temperature ranging from about 50° C. to the boiling point of the solvent used. The reaction time is varied depending on the reaction temperature and the degree of contact between the reaction solvent and hydrogen gas, namely the degree of shaking or agitation, but it is sufficient if the reaction is conducted for about 5 to about 10 hours.

It has been found that this reaction can be accelerated and the yield of the intended compound J can be increased; if a small amount of such a compound as hydrochloric acid or perchloric acid is added. It is preferred that such compound be added in an amount of 1 to 5 moles per mole of the compound to be reduced.

The reaction pressure has no substantial influence on the reaction rate or the yield of the intended compound, but it is preferred that the reaction be carried out at a pressure of up to about 10 atmospheres.

The fact that compounds of this invention represented by the following general formula: ##STR33## are 4-benzazonine derivatives having a "7-membered ring" has been confirmed by the following tests.

For example, when 4-(N-methylaminoethyl)-3, 4-dihydronaphthalen-1(2H)-one hydrochloride or 6-methoxy-4-methyl-4-(N-methylaminoethyl)-3, 4-dihydronaphthalen-1(2H)-one hydrochloride was reacted with formaldehyde, the product was converted to a picrate and was purified and subjected to elementary analysis, there was indicated a composition represented by the formula C₁₄ H₁₇ ON or C₁₆ H₂₁ O₂ N.

Further, in IR spectra (see FIGS. 1 and 2) and NMR spectra (see FIGS. 3 and 4) of the above compounds, no absorption inherent of the > NH group was present and from these spectra, it was confirmed that the above compounds have > C═O and > NCH₃ groups.

Compounds of this invention represented by the above general formula are generally insoluble in water, but they are readily rendered water-soluble merely by converting them to acid salts according to customary procedures. Either inorganic acids or organic acids can be used for this purpose. As the inorganic acid, there can be mentioned, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and as the organic acid, there can be mentioned, for example, maleic acid, citric acid, butyric acid and methanesulfonic acid.

Compounds of this invention represented by the above general formula are of low toxicity as compared with known compounds and have therapeutic activities on the central nervous system. They are very valuable as analgesics, antitussives and sedatives. Further, various compounds having similar activities can be derived from the compounds of this invention.

Results of comparative tests where the medicinal effects of compounds of this invention were compared with those of known compounds such as pentazocine and codeine phosphate by employing mice and guinea pigs as the test animals are shown in the following Tables I and II.

                                      Table I                                      __________________________________________________________________________     Compounds of Formula                                                            ##STR34##                                                                     __________________________________________________________________________                            Chemical Stimulus Method .sup.1)                                                              Heat Stimulus Method .sup.2)                      R'.sub.3     (Writhing Method)                                                                             (Hot Plate Method)                        R   R.sub.1                                                                           R.sub.2                                                                          (CH.sub.2R.sub.3)                                                                        R.sub.4                                                                           (interabdominal injection)                                                                    (hypodermic injection)                    __________________________________________________________________________     H   H  H CH.sub.2 CHCH.sub.2                                                                      OH 1.2            1.4                                       H   H  H                                                                                 ##STR35##                                                                               OH 1.2            1.2                                       H   H  H CH.sub.2 CH.sub.2                                                                        OH 1.8            4.5                                       H   CH.sub.3                                                                          H CH.sub.3  OH 0.7            1.4                                       H   CH.sub.3                                                                          H CH.sub.2 CHCH.sub.2                                                                      OH 1.8            1.5                                       H   CH.sub.3                                                                          H                                                                                 ##STR36##                                                                               OH 1.5            1.5                                       CH.sub.3 O                                                                         CH.sub.3                                                                          H CH.sub.3  OH 1.5            5.0                                       CH.sub. 3 O                                                                        CH.sub.3                                                                          H CH.sub.2 CHCH.sub.2                                                                      OH 1.4            1.6                                                                      Acute Toxicity                                                                 LD.sub.50, mg/Kg                                Compounds of Formula                                                                         Pressure Stimulus Method.sup.3)                                                                 (mouse, intrave-                                R             (hypodermic injection)                                                                          nous injection)                                                                           Remarks                              __________________________________________________________________________     H             1.4              58.0                                            H             1.4              60.0                                            H             2.0              45.0                                            H             1.2              70.0                                            H             2.0              55.0                                            H             1.6              25.0                                            CH.sub.3 O    1.2              72.0                                            CH.sub.3 O                     61.0                                            R      R.sub.1  R.sub.2                                                                              R'.sub.3    R.sub.4                                                                             1)   2)                                 __________________________________________________________________________     CH.sub.3 O                                                                            CH.sub.3 H                                                                                     ##STR37##  OH   1.6  2.2                                H      CH.sub.3 CH.sub.3                                                                             CH.sub.3    OH   1.6  2.0                                H      H        H     CH.sub.2 CHCH.sub.2                                                                        H    1.4  5.0                                H      H        H                                                                                     ##STR38##  H    1.0  1.5                                H      H        H     CH.sub.2 CH.sub.2                                                                          H    0.8  5.0                                CH.sub.3 O                                                                            CH.sub.3 H     CH.sub.3    H    0.3  2.0                                HO     CH.sub.3 H     CH.sub.3    H    1.5  2.0                                H      H        H     CH.sub.3    H    2.5  0.6                                H      H        H     CH.sub.2    H    1.0  3.0                                HO     CH.sub.3 H     CH.sub.2 CH.sub.3                                                                          H    1.5  2.0                                CH.sub.3 O                                                                            CH.sub.3 H     CH.sub.2 CH.sub.3                                                                          H    0.8  2.0                                CH.sub.3 O                                                                            CH.sub.3 CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                          H    0.8  2.0                                HO     CH.sub.3 H                                                                                     ##STR39##  H    1.0  1.5                                CH.sub.3 O                                                                            CH.sub.3 H     CH.sub.2 CH.sub.2                                                                          H    1.5  2.0                                HO     CH.sub.3 H                                                                                     ##STR40##  H    1.0  1.5                                       pentazocine                     1.0  1.0                                Compounds of Formula                                                           R                3)      Acute Toxicity                                                                               Remarks                                 __________________________________________________________________________     CH.sub.3 O       1.8     45.0                                                  H                1.5     30.0          trans-form                              H                1.5     45.0                                                  H                1.4     65.0                                                  H                2.0     35.0                                                  CH.sub.3 O               120.0                                                 HO                       75.0                                                  H                        20.0                                                  H                        120.0                                                 HO                       80.0                                                  CH.sub.3 O               120.0                                                 CH.sub.3 O               100.0         trans-form                              HO                       40.0                                                  CH.sub.3 O               48.0                                                  HO                       40.0                                                  pentazocine      1.0     25.0                                                  __________________________________________________________________________      Notes:                                                                         Tested Animal: mice of the ddN-series, ♂ , 20 ± 1g                     Experimental Conditions: temperature of 24 ± 1° C., relative         humidity of 65 ± 3%                                                         .sup.1) R. Koster, M. Anderson and E. J. De Beer, Federation Proceedings,      18, 412 (1959)                                                                 .sup.2) G. Woolfe and A. D. MacDonald; Journal of Pharmacology and             Experimental Therapeutics, 80, 300 (1944)                                      .sup.3) A. F. Green, P. A. Young and R. I. Godfrey; British Journal of         Pharmacology and Chemotherapy, 6, 572 (1951)                             

                                      Table II                                     __________________________________________________________________________      Compounds of Formula                                                           ##STR41##                 Comparison of Antitusive Effects Mechanical                                   Stimulus Method     Chemical Stimulus                                                             Method.sup.2)                     __________________________________________________________________________                 R.sub.3               Effect Ratio to    Effect Ratio to           R    R.sub.1                                                                            R.sub.2                                                                           (CH.sub.2R.sub.3)                                                                        R.sub.4                                                                            ED.sub.50, mg/kg                                                                       Codeine Phosphate                                                                         ED.sub.50,                                                                             Codeine                   __________________________________________________________________________                                                          Phosphate                 CH.sub.3 C                                                                          CH.sub.3                                                                           H  CH.sub.3  OH  13.72   105.5      6.06    218.8                     H    CH.sub.3                                                                           H  CH.sub.3  OH  4.42    326.9      1.64    800.7                     H    H   H  CH.sub.2CHCH.sub.2                                                                       H   7.42    195.0      12.67   104.7                     H    H   H  CH.sub.3  OH  9.21    157.1      6.58    201.4                     H    H   H  CH.sub.2CHCH.sub.2                                                                       CH  18.90   76.6       15.30   86.7                      codeine phosphate         14.47   100        13.26   100                       dihydrocodeine phosphate  4.65    310.7      2.65    500.4                     __________________________________________________________________________      .sup.1) Takagi et al modification [Journal of the pharmaceutical Society       of Japan, 80, 1497 (1960)]of the test method of H. Konzett and E. Rothlin      [Experientia,10, 472 (1954)], in which urethane was hypodermically             injected (15 mg/Kg) into guinea pigs and swine hairs were inserted into        the trachea to impart stimulus.                                                .sup.2) Takagi et al modification [Journal of the Pharmaceutical Society       of Japan, 80, 1497 (1960)] of the test method of H. Friebol, C. Reichle        and A. V. Gravenitz ]Archiv Fur experimentalle Phathologic und                 Pharmatologic, Naunyn-Schmiede-berg's, 224, 384 (1955)], in which the tes      compound was hypodermically injected into guinea pigs, 30 minutes after        the injection the guinea pigs were put into a desiccator filled with           SO.sub.2 gas and kept in the desiccator for 1 minute, then the guinea pig      were put into another vessel and the degree of coughing was examined.    

Compounds of this invention represented by the above general formula (1) can be administered orally, intestinally or non-orally according to customary procedures. The compounds of this invention can be formed into preparations suitable for administration, such as tablets, capsules, suppositories, liquid preparations (inclusive of injections), powders or the like, according to customary methods.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is an IR spectrum (liquid film method) of 4-methyl-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one.

FIG. 2 is an IR spectrum (paste method) of 1,4-dimethyl-10-methoxy-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one.

FIG. 3 is an NMR spectrum (CDCl₃ solvent) of 4-methyl-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one.

FIG. 4 is an NMR spectrum (CDCl₃ solvent) of 1,4-dimethyl-10-methoxy-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one.

FIG. 5 is an IR spectrum (paste method) of 4-benzyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine.

FIG. 6 is an IR spectrum (paste method) of 4-(γ-dimethylallyl)-1-methyl-10-methoxy-2,3,4,5,6,7-hexahydro-1, 6-methano-1H-4-benzazonin-7-ol.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Process for Synthesis of Compound A EXAMPLE 1

25 g of 4-(N-methylaminoethyl)-3,4-dihydronaphthalene-1(2H)-one hydrochloride was dissolved in 400 ml of methanol, and 17g of 3% formalin was added to the solution. The mixture was allowed to stand still at 40° C for 48 hours, and methanol was distilled from the reaction mixture. The residue was made alkaline with sodium hydroxide and extracted with ether. The ether extract was dried and filtered, and ether was distilled from the filtrate. The residual oily product was subjected to vacuum distillation and a fraction boiling at 130° to 137° C under 1.5 mmHg was collected to obtain 13g of a yellow oil. This was 4-methyl-2,3,4,5-tetrahydro-1, 6-methano-1H-4-benzazonin-7(6H)-one, and the melting point of the picrate was 176 to 178° C (decomposition).

EXAMPLE 2 TO 8

Reactants indicated in Table III were treated in the same manner as in Example 1 to obtain products shown in Table III. The products had boiling points or melting points shown in Table III.

                                      Table III                                    __________________________________________________________________________        Reactant [4-(N-methyl-                                                         aminoethyl)-3,4-dihydro-                                                    Ex.                                                                               naphthalene-1(2H)-one     Boiling and Melting                               No.                                                                               hydrochloride]                                                                              Product      Point                                             __________________________________________________________________________         ##STR42##                                                                                   ##STR43##   b.p.160-165° C/0.85 mm m.p.                                             69-71° C. picrate,m.p.207-209°                                   C (decomposition)                                 3                                                                                  ##STR44##                                                                                   ##STR45##   b.p.170-180° C.(bath temperature)/0.7                                   mmHg                                              4                                                                                  ##STR46##                                                                                   ##STR47##   b.p.165-170° C./ 0.7 mmHg m.p.                                          82-84° C.                                  5                                                                                  ##STR48##                                                                                   ##STR49##   b.p.175-185° C.(bath temperature)/0.2                                   mmHg                                              6                                                                                  ##STR50##                                                                                   ##STR51##   b.p.130-140° C./1.5 mmHg                   7                                                                                  ##STR52##                                                                                   ##STR53##   b.p.154-156° C.(bath temperature)/1                                     mmHg                                              8                                                                                  ##STR54##                                                                                   ##STR55##   b.p.143-146° C./0.5                        __________________________________________________________________________                                  mmHg                                         

Process for Synthesis of Compound B EXAMPLE 9

A solution consisting of 2 g of 4-methyl-2,3,4,5-tetrahydro-1,6-methano-1H-4-Benzazonin-7(6H)-one and 10 ml of methanol was added dropwise to a solution consisting of 1 g of sodium boron hydride and 15 ml of methanol over a period of 30 minutes. The mixture was agitated for 1.5 hours at room temperature, and heated and refluxed for 30 minutes. Methanol was distilled from the reaction mixture liquid and the residue was diluted with water and then extracted with ether. Ether was distilled from the ether extract and the residue was subjected to vacuum distillation to obtain 1.6 g of a fraction boiling at 155° to 166° C. under 0.7 mmHg. The product was 4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol. The melting point of the picrate was 214° to 217° C. (decomposition) and the melting point of the hydrochloride was 238° to 242.5° C.

EXAMPLE 10

6.8 g of 4.12-dimethyl-1-ethyl-10-methoxy-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one was dissolved in 400 ml of acetic acid, and 2.5 g of Adams platinum was added to the solution and hydrogenation was carried out at room temperature and atmospheric pressure. The reaction mixture liquid was filtered, and acetic acid was distilled under reduced pressure. The residue was dissolved in water, made alkaline with sodium bicarbonate and extracted with ether. Ether was distilled from the extract and the residue was subjected to vacuum distillation to obtain 6 g of light yellow oil of 4,12-dimethyl-1-ethyl-10-methoxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol boiling at 215° to 225° C. (bath temperature) under 15 mmHg. The product was converted to a hydrochloride and recrystallized from isopropanol to obtain a white crystal of the trans-1-ethyl-12-methyl type melting at 175° to 185° C. (decomposition). When ether was added to the mother liquid which had been concentrated, a crystal of the cis-1-ethyl-12-methyl type was obtained. This crystal was very hygroscopic.

EXAMPLES 11 TO 16

Mixtures containing reactants and reducing agents indicated in Table IV were treated in the same manner as in Example 9 to obtain products shown in Table IV. Melting points and boiling points of the products are also shown in Table IV.

                                      Table IV                                     __________________________________________________________________________        Reactant [4-                                                                Ex.                                                                               benzazonin-7(OH)-                                                                            Reducing           Boiling or                                 No.                                                                               one]          Agent                                                                               Product       Melting Point                                                                           Remarks                           __________________________________________________________________________     11                                                                                 ##STR56##    LiAlH.sub.4                                                                          ##STR57##    m.p.45-147° C hydrochloride,                                            m.p.205-210° C. (decomposition)     12                                                                                 ##STR58##    LiAlH.sub.4                                                                          ##STR59##    b.p.200-215° C. (bath tempe-                                            rature)/2 mmHg hydrochloride (trans-fo                                         rm), m.p.190-200° C. (decomposi                                         tion)    hydrochlo- ride(cis- form)                                                     being hygroscopic                 13                                                                                 ##STR60##    NaBH.sub.4                                                                           ##STR61##    b.p.200-210° C. (bath tempe-                                            rature)/2.5 mmHg hydrochloride,                                                m.p.190-200° C. (decomposition)     14                                                                                 ##STR62##    NaBH.sub.4                                                                           ##STR63##    m.p.102-105° C. hydrochloride,                                          .p.219-220° C.                      15                                                                                 ##STR64##    NaBH.sub.4                                                                           ##STR65##    b.p.160 -170° C. (bath tempe-                                           rature)/0.5 mmHg hydrochloride                                                 (trans-form), m.p.205-210° C.                                           (decomposition)                                                                         hydrochlori- de(cis- form)                                                     being hygroscopic                 16                                                                                 ##STR66##    NaBH.sub.4                                                                           ##STR67##    b.p.134- 143° C./ 0.5               __________________________________________________________________________                                         mmHg                                  

PROCESS FOR SYNTHESIS OF COMPOUND C EXAMPLE 17

60 g of 57% hydriodic acid, 4.5 g of red phosphorus, 18 ml of water and 25 g of glacial acetic acid were added to 20 g of 1,4-dimethyl-10-methoxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol, and the mixture was heated and refluxed for 4 hours. The reaction mixture liquid was cooled and filtered, and the filtrate was subjected to distillation under reduced pressure. The residue was dissolved in a small amount of water and neutralized with aqueous ammonia. The precipitated crystal was recovered by filtration, washed with water and dried to obtain 7.8 g of a crystal of 1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine. The crystal was dissolved in ethanol and hydrobromic acid was added to the solution. The mixture was treated with fine carbon and filtered. The filtrate was concentrated and ether was added thereto to precipitate a white crystal of the hydrobromide melting at 207° to 210° C.

EXAMPLE 18

70 g of 57% hydrobromic acid, 5.5 g of red phosphorus and 18 ml of water were added to 17 g of 1,4-dimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol, and the mixture was heated and refluxed for 3 hours. The reaction mixture liquid was cooled and filtered, and the filtrate was subjected to distillation under reduced pressure. The residue was made alkaline with sodium hydroxide and extracted with ether. The ether extract was dried and filtered, and ether was distilled from the extract. The residue was subjected to vacuum distillation to obtain 8 g of 1,4-dimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine boiling at 160° to 170° C. (bath temperature) under 3 mmHg in the form of a colorless oily product. When the hydrochloride was recrystallized from isopropyl alcohol, the melting point of the recrystallized product was 225° to 230° C.

EXAMPLES 19 TO 23

Mixtures of reactants and dehydroxylating agents indicated in Table V were treated in the same manner as in Example 17 to obtain products shown in Table V. Boiling or melting points of the products are also shown in Table V.

                                      Table V                                      __________________________________________________________________________     Ex.                                                                               Reactant [4-benz-                                                                             Dehydroxylat-           Boiling or                           No.                                                                               azonin-7-ol]   ing Agent                                                                               Product        Melting Point                                                                               Remarks                 __________________________________________________________________________     19                                                                                 ##STR68##     hydrobromic acid red phosphorus water                                                    ##STR69##     b.p. 93-97° C./0.7 mmHg                                                 hydrochloride, m.p.152-                                                        154° C. hydrobromide,                                                   m.p.249-254° C.               20                                                                                 ##STR70##     hydriodic acid red phosphorus glacial acetic acid                                        ##STR71##     hydrobromide (trans- form),m.p.1                                               87-192° C.                                                                           cis-form being                                                                 hygroscopic             21                                                                                 ##STR72##     "                                                                                        ##STR73##     hydrobromide,                                                                  m.p. 186-190°0 C.             22                                                                                 ##STR74##     "                                                                                        ##STR75##     hydrobromide (trans- form),m.p.                                                175- 180° C.                                                                         cis-form being                                                                 hygroscopic             23                                                                                 ##STR76##     "                                                                                        ##STR77##     hydrobromide (trans- form),m.p.                                                187- 192° C.                                                                         cis-form being                                                                 hygroscopic             __________________________________________________________________________

Process for Synthesis of Compound D (Method 4-I(a)) EXAMPLE 24

1.87 g of 2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine, 1.25 g of sodium bicarbonate and 1.33 g of allyl bromide were added into 30 ml of methanol, and the mixture was refluxed for 5 hours and subjected to distillation under reduced pressure. The residue was dissolved in 15 ml of 10% hydrochloric acid. The solution was washed once with 5 ml of benzene, and the water layer was made alkaline with sodium hydroxide and extracted with ether. Ether was distilled from the ether extract and the residue was subjected to vacuum distillation to obtain 2 g of a colorless oily substance as a fraction boiling at 110° to 120° C. (bath temperature) under 0.7 mmHg. The product was dissolved in 15 ml of ether and gaseous hydrochloric acid was blown into the solution to form a white precipitate. The precipitate was recovered by filtration and dried to obtain 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine hydrochloride. Recrystallization from isopropanol gave a white crystalline powder melting at 212.5° to 214.5° C.

Synthesis of Compound D (Method 4-1(b) EXAMPLE 25

1.9 g of 2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine was dissolved in 20 ml of benzene, and 1.5 g of triethylamine was added to the solution. Then, 1g of acetyl chloride was added dropwise to the mixture under ice cooling and agitation. After completion of the dropwise addition, the reaction mixture liquid was agitated at room temperature for 2 hours and 20 ml of cold 10% hydrochloric acid was added to the mixture. The mixture was agitated, and the benzene layer was separated. The separated benzene layer was washed once with 10 ml of 5% aqueous ammonia, dried and filtered, and benzene was distilled from the filtrate. The residue was dissolved in 20 ml of dioxane, and 0.7 g of lithium aluminum hydride was added to the solution and the mixture was heated and refluxed for 6 hours. The resulting mixture was cooled and several milliliters of water was added thereto. The mixture was extracted with chloroform and chloroform was distilled from the chloroform extract. The residue was subjected to vacuum distillation to obtain 1.3 g of a fraction boiling at 100° to 120° C. (bath temperature) under 0.8 mmHg. The product was a colorless oily substance. The product was dissolved in 3 ml of hydrochloric acid-saturated isopropanol and the solution was cooled with ice to precipitate 4 -ethyl-2,3,4,5,6,7-hexahydro-1,6-mathano-1H-4-benzazoine hydrochloride in the form of a white crystal. The crystal was recovered by filtration and dried, and when the melting point was determined, it was found that the product had a melting point of 237° to 239° C.

EXAMPLES 26 TO 42

Reactants indicated in Table VI were treated according to the methods (a), (b) and (c) of the process 4-I disclosed in Examples 25 and 26 and the text of the instant specification, to obtain products shown in Table VI. The melting or boiling points of the products are also shown in Table VI.

                                      Table VI                                     __________________________________________________________________________                     Alkyl Halide,                                                  Ex.             Acid Halide                  Boiling or                        No.                                                                               Reactant     or Aldehyde                                                                               Product           Melting Point                                                                              Remarks               __________________________________________________________________________     26                                                                                 ##STR78##   BrCH.sub.2 CHCH.sub.2                                                                      ##STR79##        b.p.155-175° C.(bath                                                    temperature)/1                                                                             Method (a)            27                                                                                 ##STR80##                                                                                   ##STR81##                                                                                 ##STR82##        m.p. 185-191°                                                                       Method (a)            28                                                                                 ##STR83##                                                                                   ##STR84##                                                                                 ##STR85##        m.p.115-125° C.                                                                     Method (a)            29                                                                                 ##STR86##                                                                                   ##STR87##                                                                                 ##STR88##        b.p.140-150° C.(bath                                                    temperature)/0.7 mmHg.                                                         hydrochloride, m.p.182-188.de                                                  gree. C.    Method (a)            30                                                                                 ##STR89##   BrCH.sub.2 CHCH.sub.2                                                                      ##STR90##        b.p.160 -180° C./1                                                      mmHg.       Method                __________________________________________________________________________                                                              (a)                                   Alkyl Halide,                                                  Ex.             Acid Halide                                                                              Reducing             Boiling or                      No.                                                                               Reactant     or Aldehyde                                                                              Agent                                                                               Product         Melting Point                                                                            Remarks               __________________________________________________________________________     31                                                                                 ##STR91##                                                                                   ##STR92##                                                                               LiAlH.sub.4                                                                          ##STR93##      hydrochloride, m.p.189-190.                                                    degree. C.                                                                               Method (b)            32                                                                                 ##STR94##                                                                                   ##STR95##                                                                               LiAlH.sub.4                                                                          ##STR96##      hydrochloride, m.p.235-240.                                                    degree. C.                                                                               Method (b)            33                                                                                 ##STR97##   ClCOCH.sub.2 CH.sub.2 CH.sub.3                                                           LiAlH.sub.4                                                                          ##STR98##      b.p.144- 145° C./1                                                      mmHg.     Method (b)            34                                                                                 ##STR99##                                                                                   ##STR100##                                                                              LiAlH.sub.4                                                                          ##STR101##     m.p.88-98° C.                                                                     Method (b)            35                                                                                 ##STR102##  ClCOCH.sub.3                                                                             LiAlH.sub.4                                                                          ##STR103##     hydrochloride (transform),                                                     .p.172-177°                                                                       Method (b)            36                                                                                 ##STR104##                                                                                  ##STR105##                                                                              LiAlH.sub.4                                                                          ##STR106##     hydrochloride, m.p.145-150.                                                    degree.  C.                                                                              Method (b)            37                                                                                 ##STR107##  ClCOCH.sub.2 CH.sub.2 CH.sub.3                                                           LiAlH.sub.4                                                                          ##STR108##     hydrobromide, m.p.157-158.d                                                    egree. C. Method (b)            38                                                                                 ##STR109##                                                                                  ##STR110##                                                                              HCOOH                                                                                ##STR111##     b.p.165-175°                                                            C.(bath temperature)/ 0.7                                                      mmHg.     Method (c)            39                                                                                 ##STR112##  ClCOCH.sub.3                                                                             LiAlH.sub.4                                                                          ##STR113##     hydrochloride, m.p.190-195.                                                    degree. C.                                                                               Method (b)            40                                                                                 ##STR114##  ClCOCH.sub.2 CH.sub.3                                                                    LiAlH.sub.4                                                                          ##STR115##     b.p.120-130°                                                            C.(bath temperature)/0.8                                                       mmHg. hydrochloride,                                                           m.p.222-224°                                                                      Method (b)            41                                                                                 ##STR116##                                                                                  ##STR117##                                                                              LiAlH.sub.4                                                                          ##STR118##     hydrochloride (trans-form),                                                     m.p.173-178°                                                                     Method (b)            42                                                                                 ##STR119##  ClCOCH.sub.2 CH.sub.3                                                                    LiAlH.sub.4                                                                          ##STR120##     hydrochloride (trans-form),                                                     m.p.157-162°                                                                     Method                __________________________________________________________________________                                                              (b)              

Process for Synthesis of Compound D (Method 4-II) EXAMPLE 43

30 ml of ethanol and 3 drops of hydrochloric acid were added to 300 mg of 4-phenethyl-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7-(6H)-one, and then, 0.4 g of palladium-carbon (5% palladium) was added to the mixture. The resulting solution was heated at about 70° C. and hydrogen gas was introduced thereinto for 6 hours under shaking at atmospheric pressure to effect the reduction.

The reaction mixture liquid was cooled and filtered, and ethanol was distilled from the filtrate. The residue was dissolved in a small amount of water, and the solution was made alkaline with aqueous ammonia. The released base was extracted with ether. The ether extract was dried with anhydrous potassium carbonate, and ether was distilled and the residue was subjected to vacuum distillation to thereby obtain about 0.2 g of a colorless oily product of 4-phenethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine in the form of a fraction boiling at 180° to 190° C. (bath temperature) under 1 mmHg. The hydrochloride of the product was recrystallized from isopropanol and the recrystallized product was found to have a melting point of 235° to 240° C.

EXAMPLES 44 to 47

Reactants and catalysts indicated in Table VII were treated in the same manner as described in Example 43 to obtain products shown in Table VII. The boiling or melting points of the products are also shown in Table VII.

                                      Table VII                                    __________________________________________________________________________     Ex.                                                                               Reactant(4-Benz-                                                                               Catalyst, Solvent          Boiling or                       No.                                                                               azonine-7(6H)-on)                                                                              and Promotor                                                                              Product         Melting Point                    __________________________________________________________________________     44                                                                                 ##STR121##     palladium-carbon (5% Pd) glacial acetic acid 75%                               perchloric acid                                                                            ##STR122##     m.p. 88-98° C.            45                                                                                 ##STR123##     palladium-carbon (5% Pd) ethanol 35% hydrochloric                                          ##STR124##     b.p.160-180° C.                                                         (bath temperature)/1 mmHg.       46                                                                                 ##STR125##     palladium-carbon (5% Pd) ethanol 35% hydrochloric                                          ##STR126##     hydrochloride, m.p.210-214.d                                                   egree. C.                        47                                                                                 ##STR127##        "                                                                                       ##STR128##     b.p.170-200° C.(bath                                                    emperature)/0.6                  __________________________________________________________________________                                                   mmHg.                       

Process for Synthesis of Compound E (Method 5-I(a)) EXAMPLE 48

20 ml of methanol was added to 1g of 2,3,4,5,6,7-hexahydro-1,6-methanol-1H-4-benzazoin-7-ol and 0.625 g of sodium bicarbonate, and the mixture was heated and refluxed. Then, 0.72 g of allyl bromide was gradually added dropwise to the mixture, and the reaction mixture liquid was heated and refluxed for 5 hours. The mixture was then cooled and filtered, and methanol was distilled under reduced pressure from the filtrate. Recrystallization of the residue from cyclohexane gave 0.95 g of 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol in the form of a white crystal melting at 98° to 100° C. The product was converted to a hydrochloride and recrystallized from isopropanol. The recrystallized hydrochloride was water soluble and found to have a melting point of 194° to 198° C.

EXAMPLES 49 to 58

The reaction was conducted in the same manner as in Example 48 (method 5-I(a)) by employing reactants shown in Table VIII, to obtain results shown in Table VIII.

                                      Table VIII                                   __________________________________________________________________________     Ex.                                                                               Reactant (4-benz-                           Boiling or                      No.                                                                               azonin-7-ol)    Alkyl Halide                                                                               Product         Melting Point                                                                            Remarks               __________________________________________________________________________     49                                                                                 ##STR129##     BrCH.sub.2 CHCH.sub.2                                                                       ##STR130##     m.p.124-125°                                                                      method (a)            50                                                                                 ##STR131##     BrCH.sub.2 CHCH.sub.2                                                                       ##STR132##     b.p.170-180° C.                                                         (bath temperature)/ 1                                                                    method (a)            51                                                                                 ##STR133##                                                                                     ##STR134##                                                                                 ##STR135##     m.p.134-136°                                                                      method (a)            52                                                                                 ##STR136##                                                                                     ##STR137##                                                                                 ##STR138##     m.p.155-156°                                                                      method (a)            53                                                                                 ##STR139##                                                                                     ##STR140##                                                                                 ##STR141##     hydrochloride, m.p.178-181.                                                    degree. C. (decomposition)                                                               method (a)            54                                                                                 ##STR142##                                                                                     ##STR143##                                                                                 ##STR144##     m.p.72-75° C.                                                                     method (a)            55                                                                                 ##STR145##                                                                                     ##STR146##                                                                                 ##STR147##     m.p.152-153°                                                                      method (a)            56                                                                                 ##STR148##                                                                                     ##STR149##                                                                                 ##STR150##     b.p.140-160°                                                            C.(bath temperature)/1                                                         mmHg.     method (a)            57                                                                                 ##STR151##     ClCH.sub.2 CH.sub.2 OH                                                                      ##STR152##     m.p.55-58.5°                                                                      method (a)            58                                                                                 ##STR153##     ClCH.sub.2 CH.sub.2 OH                                                                      ##STR154##     hydrochloride (trans-form),                                                     m.p.220-227°                                                                     method                __________________________________________________________________________                                                              (a)              

Process for Synthesis of Compound E (Method 5I(b)) EXAMPLE 59

20 ml of anhydrous toluene was added to 1 g of 2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol and 2 g of triethylamine, and 1g of phenylacetyl chloride was added dropwise to the mixture over a period of 30 minutes under ice cooling and agitation. After completion of the dropwise addition, the mixture was agitated for 1 hour at room temperature. Then, the reaction mixture liquid was washed twice with 50 ml of ice water, twice with 50 ml of 3% hydrochloric acid and once with 15% sodium hydroxide. The toluene layer was dried with anhydrous sodium sulfate and toluene was distilled therefrom under reduced pressure. The residue was dissolved in 20 ml of anhydrous ether, and the solution was heated and refluxed together with 0.15 g of lithium aluminum hydride powder for 6 hours. Excess lithium aluminum hydride was decomposed with ethyl acetate, and 40 ml of a saturated aqueous solution of Rochelle salt was added and the mixture was shaken. The ether layer was separated and ether was distilled from the ether layer, and the residue was converted to a hydrobromide and recrystallized from isopropanol, to obtain about 0.8 g of 4-phenethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-benzazonin-7-ol hydrobromide in the form of a white crystal melting at 203° to 205° C. (decomposition). The product was water-soluble.

EXAMPLES 60 TO 64

With use of reactants shown in Table IV, the reaction was conducted in the same manner as in Example 59 (method 5-I(b)), to obtain results shown in Table IX.

                                      Table IX                                     __________________________________________________________________________     Ex.                                                                               Reactant(4-benz-        Reducing               Boiling                                                                                Re-                  No.                                                                               azonin-7-ol) Acid Halide                                                                               Agent                                                                               Product           Melting                                                                                marks                __________________________________________________________________________     60                                                                                 ##STR155##                                                                                  ##STR156##                                                                               LiAlH.sub.4                                                                          ##STR157##       m.p.123-126°                                                                    Method (b)           61                                                                                 ##STR158##  ClCOCH.sub.3                                                                              LiAlH.sub.4                                                                          ##STR159##       hydrochloride, m.p.192-1                                                       95°                                                                     C. (decomposition)                                                                     Method (b)           62                                                                                 ##STR160##  ClCOCH.sub.2 CH.sub.3                                                                     LiAlH.sub.4                                                                          ##STR161##       hydrochloride, m.p.180-1                                                       90° C. (compositi                                                       on)     Method (b)           63                                                                                 ##STR162##  ClCOCH.sub.2 CH.sub.2 CH.sub.3                                                            LiAlH.sub.4                                                                          ##STR163##       hydrochloride (trans-for                                                       m), m.p.140-150°                                                        C. (decomposition)                                                                     Method (b)           64                                                                                 ##STR164##                                                                                  ##STR165##                                                                               LiAlH.sub.4                                                                          ##STR166##       hydrochloride, m.p.192-1                                                       99.5° C.                                                                        Method (b)           __________________________________________________________________________

Process for Synthesis of Compound E (Method 5-II(a)) EXAMPLE 65

20 ml of ethanol was added to 1 g of 2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one and 0.63 g of sodium carbonate, and the mixture was heated and refluxed. Then, 0.72 g of allyl bromide was gradually added to the mixture, and the reaction mixture liquid was heated and refluxed for 5 hours. The mixture was cooled and filtered, and methanol and excessive allyl bromide were distilled from the filtrate. The residue was dissolved in 20 ml of methanol and cooled with ice water, and 0.15 g of sodium boron hydride was gradually added to the solution under agitation. Then, the mixture was agitated at room temperature for 2 hours. Methanol was distilled from the reaction mixture, and 15 ml of water was added to the residue and the mixture was shaken sufficiently. Then, the mixture was extracted with ether and the extract was subjected to distillation to remove ether therefrom. The residue was recrystallized from cyclohexane to obtain 0.9 g of 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4 -benzazonin-7-ol in the form of a white crystal melting at 98° to 100° C.

The product was converted to a hydrochloride and recrystallized from isopropanol. The melting point of the recrystallized hydrochloride was 194° to 198° C.

Process for Synthesis of Compound E (Method 5-II(b)) EXAMPLE 66

20 ml of anhydrous toluene was added to 1 g of 2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one and 2 g of triethylamine, and 1 g of phenylacetyl chloride was added dropwise to the mixture over a period of 30 minutes under ice cooling and agitation. After completion of the dropwise addition, the mixture was agitated for 1 hour at room temperature. The reaction mixture liquid was washed twice with 50 ml of water and the toluene layer was dried with anhydrous sodium sulfate and filtered. Toluene was removed from the filtrate by distillation under reduced pressure, and the residue was dissolved in 20 ml of anhydrous dioxane and the solution was heated and refluxed for 6 hours together with 0.3 g of lithium aluminum hydride. Then, excess lithium aluminum hydride was decomposed with drops of ethyl acetate, and 50 ml of saturated aqueous solution of Rochelle salt was added and the mixture was shaken. The resulting solution was extracted with ether, and the ether extract was subjected to distillation to remove ether therefrom. The residue was subjected to vacuum distillation to obtain 0.9 g of a fraction of 4-phenethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol boiling at 148° to 152° C. (bath temperature) under 1 mmHg. The product was a light-yellow oil.

The hydrobromide of the product was recrystallized. The melting point of the recrystallized hydrobromide was 203° to 205° C. (decomposition).

EXAMPLES 67 TO 79

Reactants shown in Table X were treated in the same manner as described in Example 65 or 66 (method (a) or (b)), to obtain results shown in Table X.

                                      Table X                                      __________________________________________________________________________        Reactant              Pro-                                                  Ex.                                                                               (4-benzazonin-                                                                           Alkyl Halide                                                                               ducing                Boiling or                      No.                                                                               7(6H)-one)                                                                               or Acid Halide                                                                             Agent                                                                              Product           Melting Point                                                                            Remarks               __________________________________________________________________________     67                                                                                 ##STR167##                                                                              BrCH.sub.2 CHCH.sub.2                                                                      NaBH.sub.4                                                                          ##STR168##       m,p.117-120°                                                                      method (a)            68                                                                                 ##STR169##                                                                              BrCH.sub.2 CHCH.sub.2                                                                      NaBH.sub.4                                                                          ##STR170##       b.p.170-180°                                                            C.(bath temperature)/1mmHg                                                               method (a)            69                                                                                 ##STR171##                                                                              BrCH.sub. 2 CHCH.sub.2                                                                     LiAlH.sub.4                                                                         ##STR172##       m.p.124-125°                                                                      method (a)            70                                                                                 ##STR173##                                                                               ##STR174## NaBH.sub.4                                                                          ##STR175##       b.p.140-160°                                                            C.(bath temperature)/1mmHg.                                                              method (a)            71                                                                                 ##STR176##                                                                               ##STR177## NaBH.sub.4                                                                          ##STR178##       m.p.155-156°                                                                      method (a)            72                                                                                 ##STR179##                                                                              ClCH.sub.2 CH.sub.2 OH                                                                     NaBH.sub.4                                                                          ##STR180##       hydrochloride, m.p.220-229.                                                    degree. C.                                                                               method (a)               Reactant              Re-                                                   Ex.                                                                               (4-benzazonin-                                                                           Alkyl Halide                                                                               ducing                                                                             Boiling or                                        No.                                                                               7(6H)-one)                                                                               or Acid Halide                                                                             Agent                                                                              Product           Melting Point                                                                            Remarks               __________________________________________________________________________     73                                                                                 ##STR181##                                                                               ##STR182##                                                                                     ##STR183##       hydrochloride, m.p.178-181.                                                    degree. C. (decomposition)                                                               method (a)            74                                                                                 ##STR184##                                                                              ClCH.sub.2 CH.sub.2 OH                                                                     NaBH.sub.4                                                                          ##STR185##       m.p.55-58.5°                                                                      method (a)            75                                                                                 ##STR186##                                                                              ClCH.sub.2 CH.sub.2 OH                                                                     NaBH.sub.4                                                                          ##STR187##       hydrochloride (trans-form),                                                     m.p.220-227°                                                                     method (a)            76                                                                                 ##STR188##                                                                              ClCH.sub.2 CH(OH)CH.sub.2 OH                                                               NaBH.sub.4                                                                          ##STR189##       oil       method (a)            77                                                                                 ##STR190##                                                                               ##STR191## LiAlH.sub.4                                                                         ##STR192##       m.p.123-126°                                                                      method (b)            78                                                                                 ##STR193##                                                                              ClCOCH.sub.2 CH.sub.3                                                                      LiAlH.sub.4                                                                         ##STR194##       hydrochloride, m.p.180-190.                                                    degree. C. (decomposition)                                                               method (b)            79                                                                                 ##STR195##                                                                              ClCOCH.sub.2 CH.sub.2 CH.sub.3                                                             LiAlH.sub.4                                                                         ##STR196##       hydrochloride (trans-form),                                                     m.p.140-150° C.                                                        (decomposition)                                                                          method                __________________________________________________________________________                                                              (b)              

Process for Synthesis of Compound G EXAMPLE 80

A solution consisting of 1.5 g of sodium hydroxide and 5 ml of water was added to a solution consisting of 2.5 g of 4,12-dimethyl-1-ethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine and 20 ml of methanol, and the resulting solution was cooled to 0° C. Then, 4 g of nitrosomethylurea was added to the solution and the reaction was conducted at 0° C. for 3 hours. The temperature was returned to room temperature and the reaction mixture was allowed to stand still for 2 hours. Methanol was removed by distillation under reduced pressure, and a small amount of water was added to the residue and the mixture was extracted with ether. When gaseous hydrochloric acid was introduced into the ether extract, there was obtained a white precipitate of 4,12-dimethyl-1-ethyl-10-methoxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine hydrochloride. The precipitate was recovered by filtration and dried to obtain 1.2 g of the product. When it was recrystallized from a liquid mixture of isopropanol and ether, there was obtained 0.4 g of a hydrochloride of the trans-1,12-dimethyl type melting at 172° to 177° C.

EXAMPLE 81

A solution consisting of 0.8 g of sodium hydroxide and 40 ml of methanol was added to a solution consisting of 4.3 g of trimethylphenyl ammonium bromide and 20 ml of methanol, and the mixture was allowed to stand still. The precipitated crystal was removed by filtration, and the filtrate was incorporated with 2.7 g of 10-hydroxy-1,4,12-trimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine. The mixture was heated in a water bath to distill methanol therefrom. The residue was heated in an oil bath maintained at 100° to 120° C. for 1 hour to complete the reaction. The reaction mixture was cooled, incorporated with 100 ml of acetic acid and subjected to steam distillation to completely remove dimethylaniline formed as a by-product. Then, the reaction mixture was made alkaline with sodium hydroxide and extracted with ether. When gaseous hydrochloric acid was introduced into the ether extract, there was formed a white precipitate of 10-methoxy-1,4,12-trimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine hydrochloride. The precipitate was recovered by filtration and dried to obtain 2 g of the product. When the product was recrystallized from a mixture of isopropanol and ether, 0.8 g of a hydrochloride of the trans-1,12-dimethyl type was obtained. The hydrochloride was found to have a melting point of 185° to 190° C.

EXAMPLES 82 TO 84

With use of reactants and methoxylating agents indicated in Table XI, the reaction was carried out in the same manner as described in Example 80 to 81, to obtain results shown in Table XI.

                                      Table XI                                     __________________________________________________________________________          Reactant (10-                                                             Example                                                                             hydroxy-4-benz-                                                                           Methoxylat-                Boiling or                          No.  azonine)   ing Agent       Product    Melting Point                       __________________________________________________________________________     82                                                                                   ##STR197##                                                                               CH.sub.2 N.sub.2                                                                                ##STR198##                                                                               hydrochloride,  m.p.                                                           215-22° C.                   83                                                                                   ##STR199##                                                                                ##STR200##                                                                                     ##STR201##                                                                               hydrochloride,  m.p.                                                           205-210° C.                  84                                                                                   ##STR202##                                                                                ##STR203##                                                                                     ##STR204##                                                                               hydrochloride,  m.p.                                                           190-195° C.                  __________________________________________________________________________

PROCESS FOR SYNTHESIS OF COMPOUND H EXAMPLE 85

2 g of 4-(n-butyl)-10 -methoxy-1-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine was dissolved in 30 ml of 47% hydrobromic acid, and the solution was heated and refluxed for about 1 hour. The reaction mixture was cooled and water was distilled under reduced pressure. The residue was dissolved in isopronaol, and a large quantity of ether was added thereto. The resulting mixture was allowed to stand still for a while at room temperature, whereby there was obtained 1.2 g of a white crystal of 4 -(n-butyl)10-hydroxy-1-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine hydrobromide melting at 157° to 158° C.

EXAMPLES 86 to 91

With use of reactants indicated in Table XII, the demethylation was carried out in the same manner as in Example 86, to obtain results shown in Table XII.

                                      Table XII                                    __________________________________________________________________________                                                          Boiling                      Reactant                                          or                        Ex.                                                                               (10-methoxy-4-        Demethylat-                 Melting                   No.                                                                               benzazonine)          ing Agent                                                                             Product              Point                                                                               Remarks              __________________________________________________________________________     86                                                                                 ##STR205##           hydrobromic acid                                                                       ##STR206##          hydro- bromide,                                                                m.p.192- 195°                                                           C.                        87                                                                                 ##STR207##           "                                                                                      ##STR208##          hydro- bromide                                                                 (trans- form),                                                                 m.p.175- 185°                                                           C.   cis-form being                                                                 hygro- scopic        88                                                                                 ##STR209##           "                                                                                      ##STR210##          hydro- bromide                                                                 m.p.168- 171°                                                           C.                        89                                                                                 ##STR211##           "      hydrobromic                                                                     ##STR212##          hydro- bromide                                                                 (trans- form),                                                                 m.p.141- 153°                                                           C.   cis-form being                                                                 hygro- scopic        90                                                                                 ##STR213##           "                                                                                      ##STR214##          hydro- bromide                                                                 (trans- form),                                                                 m.p.187- 192°                                                           C.   cis-form being                                                                 hygro- scopic        91                                                                                 ##STR215##           "                                                                                      ##STR216##          hydro- bromide,                                                                m.p.207- 210°                                                           C.                        __________________________________________________________________________

Process for Synthesis of Compound J EXAMPLE 92

300 ml of ethanol and 3 ml of hydrochloric acid were added to 30 g of 4-methyl-2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one to form a solution. Then, 50 g of palladium-carbon (5% palladium) was added to the solution, and the solution was heated at about 60° C. and hydrogen gas was introduced thereinto for 6 hours under shaking at atmospheric pressure to effect the reduction. The reaction mixture liquid was cooled and filtered, and ethanol was distilled from the filtrate. The residue was dissolved into 50 ml of water, and the solution was made alkaline by addition of aqueous ammonia and the released base was extracted with ether. The ether extract as dried with anhydrous potassium carbonate, and ether was removed by distillation and the residue was subjected to vacuum distillation. Thus was obtained about 20 g of a colorless oily product of 4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine boiling at 93° to 97° C. under 0.7 mmHg. The hydrochloride of the product was recrystallized from isopropanol, and the melting point of the recrystallized hydrochloride was determined. As a result it was found that the recrystallized hydrochloride had a melting point of 252.5° to 254° C. Likewise, the melting point of the hydrobromide of the product was measured and it was found that the hydrobromide had a melting point of 240° to 250° C.

EXAMPLES 93 to 98

With use of reactants shown in Table XIII, the reduction was carried out in the same manner as in Example 93, to obtain results shown in Table XIII.

                                      Table XIII                                   __________________________________________________________________________          Reactant (4-                                                              Example                                                                             benzazonin-7-                                                                              Reducing             Boiling or                               No.  one)        Agent    Product     melting Point                            __________________________________________________________________________     93                                                                                   ##STR217## glacial acetic acid, 75% per- chloric acid, palladium-                         carbon (5% Pd)                                                                           ##STR218## b.p.180-200° C. (bath                                                   temperature/ 4 mmHg hydrochloride,                                             m.p.205-210° C.                   94                                                                                   ##STR219## glacial acetic acid, 75% per- chloric acid, palladium-car                      bon (5% Pd)                                                                              ##STR220## b.p.170-180° C. (bath                                                   temperature /2 mmHg. hydrochloride                                             (trans-form), m.p.185-190°                                              C.                                       95                                                                                   ##STR221## methanol, hydrochloric acid, palla- dium-carbon (5%                                      ##STR222## b.p.180-200° C. (bath                                                   temperature /3 mmHg. hydrochloride,                                            .p.190-195° C.                    96                                                                                   ##STR223## glacial acetic acid, 75% per- chloric acid, palladium                          black                                                                                    ##STR224## b.p.180-200° C.  (bath                                                  temperature /2 mmHg. hydrochloride                                             (trans-form), m.p.172-177°                                              C.                                       97                                                                                   ##STR225## glacial acetic acid, 75% per- chloric acid, palladium-                         carbon (5% Pd)                                                                           ##STR226## b.p.160-170° C. (bath                                                   temperature /3 mmHg. hydrochloride,                                            .p.225-230° C.                    98                                                                                   ##STR227## glacial acetic acid, 75% per- chloric acid, palladium-                         carbon (5% Pd)                                                                           ##STR228## b.p.165-175° C. (bath                                                   temperature /2 mmHg. hydrochloride                                             (trans-form) m.p.163-165°         __________________________________________________________________________                                           C.                                  

In each of the foregoing Examples the melting point was measured with use of a micro melting point apparatus. 

What we claim is:
 1. A compound selected from the group consisting of a 4-benzazonine of the formula: ##STR229## and the pharmaceutically acceptable acid addition salts thereof, wherein R is hydrogen, hydroxy or alkoxy of up to 3 carbon atoms;R₁ is hydrogen or alkyl of up to 3 carbon atoms; R₂ is hydrogen, methyl or ethyl; and R₃ is hydrogen, straight or branched alkyl of up to 4 carbon atoms, straight or branched alkenyl of up to 4 carbon atoms, mono- or dihydroxyalkyl of up to 2 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, or phenylmethyl.
 2. A compound according to claim 1 whereinR is hydrogen, hydroxy or methoxy; R₁ is alkyl of 1 to 3 carbon atoms; R₂ is hydrogen, methyl or ethyl; and --CH₂ R₃ is methyl, ethyl, propyl, butyl, isopentyl, allyl, γ-dimethylallyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, cyclopropylmethyl, benzyl or phenethyl.
 3. A compound according to claim 2 which when R₂ is other than hydrogen has the cis configuration relative to R₁ and R₂.
 4. A compound according to claim 2 which when R₂ is other than hydrogen has the trans configuration relative to R₁ and R₂.
 5. A compound according to claim 2 wherein --CH₂ R₃ is methyl.
 6. A compound according to claim 5 wherein R is methoxy.
 7. A compound according to claim 1 wherein said 4-benzazonine is 10-methoxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol
 8. A compound according to claim 1 wherein said 4-benzazonine is 1,4-dimethyl-10-methoxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.
 9. A compound according to claim 1 wherein said 4-benzazonine is 1,4-dimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.
 10. A compound according to claim 1 wherein said 4-benzazonine is 4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.
 11. A compound according to claim 1 wherein said 4-benzazonine is 1,4,12-trimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.
 12. A compound according to claim 1 wherein said 4-benzazonine is 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.
 13. A compound according to claim 1 wherein said 4-benzazonine is 4-(γ-dimethylallyl)-10-methoxy-1-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.
 14. A compound according to claim 1 wherein said 4-benzazonine is 4-allyl-10-methoxy-1-methyl-2,3,4,5,6,7-hexahydro1,6-methano-1H-4-benzazonin-7-ol.
 15. A compound according to claim 1 wherein said 4-benzazonine is 1-methyl-4-phenethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol.
 16. A compound according to claim 1 wherein said 4-benzazonine is 4-cyclopropylmethyl-1-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol. 